Page1 IJPBS Volume 2 Issue 1 JAN-MARCH 212 1-11 Evaluation of Efficacy & Tolerability of Trisoliv Syrup (Andrographolides + Tricholine Citrate + Sorbitol) in the Management of Various Liver Dysfunctions. Arif A.Faruqui 1*, Chandrakant Joshi 2, Wasim Siddique 3, Rahul Mahajan 4 1* General Manager-Medical Services, Medley Pharmaceuticals Ltd., D-2, MIDC, Andheri (E), Mumbai-93 2 Manager - Medical Services, Medley Pharmaceuticals Ltd., D-2, MIDC, Andheri (E), Mumbai-93 3 Executive Trainee- Medical Services, Medley Pharmaceuticals Ltd., D-2, MIDC, Andheri (E),Mumbai-93 4 Executive Trainee- Medical Services,Medley Pharmaceuticals Ltd.,D-2, MIDC, Andheri (E), Mumbai-93 *Corresponding Author Email: drfaruqui@medleylab.com PHARMACEUTICAL SCIENCES Research Article RECEIVED ON 5-12-211 ACCEPTED ON 2-1-212 ABSTRACT Polyherbal drug formulations having hepatoprotective activity is the widely recognized and utilized therapy in the management of various liver dysfunctions. To evaluate efficacy and tolerability of Trisoliv Syrup in the management of various liver dysfunctions. Open, non-comparative, multi-centre, post marketing study. 5 patients suffering from various liver dysfunction like were enrolled in this study, 46 patients completed the study. Patients were given hepatoprotective syrup containing Andrographolides + Sorbitol + Tricholine citrate (A + S + T) 1 ml 2 to 3 times in a day for 8 weeks. The subjective clinical improvement in (jaundice symptoms, fatigue, and loss of appetite) was assessed on a predefined to 3 score scale. Total bilirubins (TB), SGOT/ AST, SGPT/ALT, serum alkaline phosphatase were assessed at baseline and end of 8 weeks. Secondary outcomes were patient s assessment about efficacy and tolerability of the hepatoprotective product Trisoliv. After 8 weeks of Trisoliv Syrup therapy 86.96% (4/46) of patients achieved the normal values for TB. As like TB, there was significant improvement in SGOT values after treatment with Trisoliv Syrup. 1 % of patients achieved normal values for SGPT/ALT and alkaline phosphatase (AP) values after 8 week of Trisoliv Syrup therapy. All the patients reported significant improvement in Jaundice, fatigue and loss of appetite on predefined to 3 score scale. On the predefined scale of global efficacy 86.96% patients reported good to excellent efficacy rating for Trisoliv Syrup. Similarly, 82.61% patients reported good to excellent ratings for tolerability. The result of the study showed that A + S + T (Trisoliv syrup) is clinically effective and safe in the management of various liver dysfunctions. KEYWORDS: Hepatitis, liver, bilirubin, SGOT, SGPT, Andrographis paniculata, sorbitol INTRODUCTION Liver disease or disorder (LD) is a global public health phenomenon that has continued to rise due to cases of excessive consumption of alcohol, inhaling of harmful gases, intake of contaminated food and drugs. While effect includes clinical symptoms like chills, fatigue, loss of appetite, dark urine, yellow sclera and conjunctiva, fever or right upper quadrant abdominal pain, Jaundice is not a disease but rather a sign that can occur in many different diseases 1. Alcoholic liver disease is a major cause of morbidity and mortality worldwide. Mortality from alcoholic cirrhosis is higher than non alcoholic and survival is 5-1 years in 7-23% with 25% of patients dying within 1 year. Alcohol can cause liver damage in the form of fatty liver, hepatitis, fibrosis, and liver cirrhosis 2. Infective hepatitis occurs endemically and sporadically throughout the world, depending on the endemicity of infection. Hepatitis A infection is common infection worldwide and human is thought to be its principal host. In developed countries, the incidence of Hepatitis A Virus (HAV) infection is low while in developing regions of the world, inadequate sanitation results in continuous transmission of HAV, especially to children and young individuals 3, 4, 5. Hepatitis B Virus (HBV) is the second most common cause of acute viral hepatitis. Hepatitis B
Page2 IJPBS Volume 2 Issue 1 JAN-MARCH 212 1-11 is a potentially life-threatening liver infection caused by the HBV. It is a major global health problem and the most serious type of viral hepatitis. Approximately 5% of the world's population is chronically infected with HBV. Approximately 2% of these individuals will eventually develop HBV-related cirrhosis or hepatocellular carcinoma (HCC). According to the World Health Organization, these HBV-related complications lead to.5 to 1.2 million deaths each year, making HBV the 1th leading cause of death worldwide. In sub-saharan Africa, the Pacific, and particularly Asia, HBV infection is highly endemic, with the majority of individuals becoming infected during childhood 6. Drugs and chemicals can cause a wide spectrum of liver injury in several ways. Some drugs are directly injurious to the liver; others are transformed by the liver into chemicals that can be injurious to the liver directly or indirectly. It is common to find liver disorders in patients exposed to medications such as antitubercular drugs, paracetamol and statins 2. Polyherbal drug formulations having hepatoprotective activity is the widely recognized and utilized therapy in the management of various liver dysfunctions. Need of Study No rational therapy is available for the cure of liver dysfunctions. At present ample studies on animals evaluating hepatoprotective effect of herbal drugs are available. Andrographolide is one of the herbal drugs obtained from Andrographis paniculata (common name: Kalmegh) with proven efficacy in various liver dysfunctions. In the present study we intend to evaluate the efficacy and tolerability of a herbal formulation Trisoliv Syrup containing andrographolides as one of the major ingredient besides Tricholine citrate and Sorbitol. Objective The present study was aimed to evaluate the efficacy and tolerability of Trisoliv Syrup (Andrographolides + Tricholine citrate + Sorbitol) in the management of various liver dysfunctions. Study design This study was an open, non comparative, post marketing study conducted at 5 centers in India. MATERIALS AND METHODS Selection of subjects Patients suffering from liver dysfunctions like jaundice and hepatitis of varied etiology confirmed with biochemical examinations (liver function tests) mentioned as below: Serum Total Bilirubin: > 1. mg/dl SGOT/AST: > 45 IU/L SGPT/ALT: > 5 IU/L Serum Alkaline Phosphatase: > 125 IU/L Inclusion criteria A total of 5 patients suffering from various liver diseases & presenting with jaundice willing to give informed consent were included in the study. Exclusion criteria Pregnant and lactating women, known severe renal insufficiency, cardiac disease and patients with history of gastritis, peptic ulcer, bleeding ulcer were excluded from the study. Follow up and monitoring Patients were advised to follow up after every 14 days for monitoring of clinical symptoms and biochemical investigation. There were 5 visits for each patient. The visit schedule was as follows. Visit 1: Day 1 = Admission to the study. Visit 2: After 2 nd Week = First Follow up visit on 14th day.
Page3 IJPBS Volume 2 Issue 1 JAN-MARCH 212 1-11 Visit 3: After 4 th Week = Second Follow up visit on 28th day. Visit 4: After 6 th Week = Third Follow up visit on 42nd day. Visit 5: After 8 th Week = Fourth Follow up visit on 56th day. At the initial visit, informed written consent was obtained from all the enrolled patients, after explaining to them the nature of the study. A detailed medical history was obtained from all enrolled patients, which was followed by thorough clinical examination. All patients were subjected to liver function tests. Trial drug and dosage administration Trisoliv Syrup: Combination of Tricholine Citrate + Andrographolides + Sorbitol (Medley Pharmaceutical Ltd. Mumbai) The patients were advised to take 2 teaspoonfuls (1 ml) of Trisoliv Syrup, orally, twice a day before meals, for 8 weeks. Patients were not allowed to take any other medication, which would have any significant effect on LFT. Concomitant medication Patient will continue all the regular medication he has been prescribed for his associated disease except those mentioned in the exclusion criteria. Investigator may modify the drug therapy, if any modification of therapy is needed for chronic ailments. Primary and secondary endpoints Biochemical investigation In each follow up visits patients were monitored for biochemical investigation of LFT by taking blood samples. For biochemical tests we have fixed the standard normal values for each parameter as follows: SGOT/AST: 1 to 45 IU/L SGPT/ALT: 1 to 5 IU/L Serum Alkaline Phosphatase: 4 to 125 IU/L The patients were monitored for the clinical symptoms of liver dysfunctions like chills, headache, malaise, anorexia, nausea, vomiting, diarrhea, upper abdominal pain, tender liver, enlarged spleen, dark urine, and yellow tint to sclera. The subjective clinical improvement in (jaundice symptoms, fatigue, and loss of appetite) was assessed on a predefined to 3 score scale (=none, 1=mild, 2=moderate, 3=severe). Dark yellow urine and yellowish appearance of skin and conjunctiva were considered as jaundice symptoms. Improvement in all clinical symptoms were monitored and recorded by physician. Global assessment of efficacy and tolerability by patients The patients who successfully completed 8 weeks of treatments were asked to fill up the global assessment scale for efficacy and tolerability. Efficacy and tolerability were assessed on a predefined five points scale of scores to 4 (=none, 1=poor, 2=average, 3=good, 4=excellent). Adverse events Each subject was carefully monitored for adverse events. All adverse events either reported by patients or observed by physicians were recorded with information about severity, duration and action taken regarding the study drug. Severities of adverse events were recorded on a scale of scores 1 to 3 (1=mild, 2=moderate, 3=severe). Outcome of action taken on adverse events were recorded on a scale of scores 1 to 4 (1= Unchanged, 2=improved, 3=resolved, 4=worsened). Serum Total Bilirubin:.12 to 1. mg/dl
Page4 STB(mg/dl) IJPBS Volume 2 Issue 1 JAN-MARCH 212 1-11 Subject dropout Patients who have not completed the 8 week study were considered as drop out cases. The reason for the drop out was recorded in CRF. Statistical analysis RESULTS Out of 5 patients enrolled in this study, 46 patients completed the study. Others were considered as drop outs. Reason for drop out was lost to follow up. Out of 46 patients 3 were male 16 were females. Average age was 43.82 years. Biochemical findings Total Bilirubin Statistical analysis was done by One-way Analysis of Variance (ANOVA) followed by Dunnett s Multiple Comparison Test. The minimum level of significance was fixed at 95% confidence limit and P<.5 was considered as significant. All the biostatistical data was performed by using Graph Pad Prism 5 version 5.3. there was significant improvement in the TB values. After 8 weeks of Trisoliv Syrup therapy 86.96% (4/46) of patients have achieved the normal values for TB, while in 13.4% (6/46) patients achieved the near normal value. Further continuation of Trisoliv Syrup therapy was recommended in those patients. Mean TB at baseline was 6.34 ± 2.24 which reduced significantly to.72 ±.29 (p<.1) at the end of therapy. In biochemical investigation of Total Bilirubin we have found that with the use of Trisoliv Syrup Table I: Effect of Trisoliv Syrup on Serum Total Bilirubin (mg/dl) Mean SD Mean Diff. P <.5 Summary 95% CI of diff 6.35 2.24 - - - - 2 nd week 4.9 1.36 2.26 Yes *** 1.62 to 2.9 4 th week 2.41.82 3.94 Yes *** 3.29 to 4.58 6 th week 1.51.44 4.84 Yes *** 4.2 to 5.49 8 th week.72.29 5.63 Yes *** 4.99 to 6.27 8 6 4 2 Week -6 Figure 1 Effect of Trisoliv Syrup on Serum Total Bilirubin (mg/dl)
Page5 SGOT/AST(IU/L) IJPBS Volume 2 Issue 1 JAN-MARCH 212 1-11 SGOT/AST As like TB, there was significant improvement in SGOT values after treatment with Trisoliv Syrup. Only 2 patients (4.35%) did not achieve the normal values of SGOT after 8 week of treatment. Trisoliv significantly reduced SGOT to 28.67 ± 8.4 from a baseline of 122.5 ± 19.7 P<.1 Table II: Effect of Trisoliv Syrup on SGOT/AST (IU/L) Mean SD Mean Diff. P <.5 Summary 95% CI of diff 122.5 19.7 - - - - 2 nd week 18.9 16.34 13.54 Yes *** 1.9-16.99 4 th week 9.17 15.31 32.3 Yes *** 28.85-35.75 6 th week 58.72 12.86 63.76 Yes *** 6.31-67.21 8 th week 28.67 8.4 93.8 Yes *** 9.35-97.25 15 1 5 Figure 2 Effect of Trisoliv Syrup on SGOT/AST (IU/L) SGPT/ALT All 46 patients achieved normal values for SGPT after 8 week of Trisoliv Syrup therapy. There was a significant decrease in SGPT values in each follow up visit.
Page6 SGPT/ALT(IU/L) IJPBS Volume 2 Issue 1 JAN-MARCH 212 1-11 Table III: Effect of Trisoliv Syrup on SGPT/ALT (IU/L) Mean SD Mean Diff P<.5 Summary 95% CI of diff 151.4 37.13 2 nd week 124.2 29.99 27.17 Yes *** 2.91-33.44 4 th week 89 25.48 62.39 Yes *** 56.13-68.66 6 th week 54.46 18.29 96.93 Yes *** 9.67-13.2 8 th week 27.43 8.65 124 Yes *** 117.7-13.2 2 15 1 5 Figure 3 Effect of Trisoliv Syrup on SGPT/ALT (IU/L) Serum Alkaline Phosphatase There was significant improvement in the AP values after 8 weeks of treatment with Trisoliv Syrup and all 46 (1%) patients achieved the normal AP values.
Page7 SAP(IU/L) IJPBS Volume 2 Issue 1 JAN-MARCH 212 1-11 Table IV: Effect of Trisoliv Syrup on Serum Alkaline Phosphatase (IU/L) Mean SD Mean Diff P<.5 Summary 95% CI of diff 214.5 33.3 2 nd week 176 25.75 38.5 Yes *** 26.47-5.53 4 th week 147 19.91 67.52 Yes *** 55.49-79.55 6 th week 117.9 18.1 96.61 Yes *** 84.58-18.6 8 th week 89.9 15.42 125.4 Yes *** 113.4-137.4 3 2 1 Figure 4 Effect of Trisoliv Syrup on Serum Alkaline Phosphatase (IU/L) Clinical Monitoring Jaundice symptoms score All the patients (1%) who were enrolled in the study showed jaundice symptoms at the time of admission. After completion of 8 weeks of therapy with Trisoliv Syrup there was significant improvement in the jaundice scores from 2.7 to.22 as showed in the table V. Table V: Effect of Trisoliv Syrup on Jaundice Symptoms score Mean SD Mean Diff. P<.5 Summary 95% CI of diff 2.7.47 2nd week 1.28.46 1.41 Yes *** 1.19-1.64 4th week 1.13.34 1.57 Yes *** 1.34-1.79 6th week.33.47 2.37 Yes *** 2.15-2.59 8th week.22.42 2.48 Yes *** 2.26-2.7
Page8 Score Score IJPBS Volume 2 Issue 1 JAN-MARCH 212 1-11 3 2 1 Figure 5 Effect of Trisoliv Syrup on Jaundice Symptoms Score Fatigue Score All the 46 (1%) patients showed fatigue at the beginning of the study. Mean score for fatigue on Table VI: Effect of Trisoliv Syrup on Fatigue score the time of admission was 2.35. After completion of 8 weeks of therapy all the patients (1%) were resolved completely from fatigue. Mean SD Mean Diff. P <.5 Summary 95% CI of diff 2.35.67 2 nd week 1.46.62.89 Yes ***.63-1.15 4 th week.48.55 1.87 Yes *** 1.61-2.13 6 th week.15.36 2.2 Yes *** 1.94-2.46 8 th week 2.35 Yes *** 2.9-2.61 3 2 1 Figure 6 Effect of Trisoliv Syrup on Fatigue Score
Page9 Score IJPBS Volume 2 Issue 1 JAN-MARCH 212 1-11 Loss of Appetite score All the 46 (1%) patients showed loss of appetite at the admission to the study. Mean score observed at the beginning was 2.74 indicating moderate to severe loss of appetite which resolved completely after 6 weeks of therapy with Trisoliv Syrup. Table VII: Effect of Trisoliv Syrup on Loss of Appetite score Mean SD Mean Diff P <.5 2.72.46 Significant Summary 95% CI of diff 2 nd week 1.26.44 1.46 Yes *** 1.28-1.63 4 th week.24.43 2.48 Yes *** 2.3-2.66 6 th week 2.72 Yes *** 2.54-2.89 8 th week 2.72 Yes *** 2.54-2.89 3 2 1 Figure 7 Effect of Trisoliv Syrup on Loss of Appetite Score Global assessment of efficacy and tolerability On the predefined scale of global efficacy 86.96% patients had given good to excellent efficacy rating for Trisoliv Syrup in the management of liver dysfunctions. Similarly, 82.61% patients had assessed good to excellent rating for tolerability. Only mild diarrhoea was reported by 2.17% (1/46) patients. No other adverse events were reported in the study and formulation was well tolerated. Discussion Liver dysfunctions are public global health problem responsible for millions of deaths per year. In the present study we evaluated the efficacy and safety of Trisoliv Syrup on various subjective (symptom score) and objective (LFT)
Page1 IJPBS Volume 2 Issue 1 JAN-MARCH 212 1-11 parameters. Trisoliv Syrup which has Tricholine interference with hepatic Very Low Density citrate, andrographolide, and sorbitol helps not Lipoprotein (VLDL) production and output 17. only in improving the LFT but also it improves the appetite and relieves symptoms associated with jaundice. These beneficial clinical effects of Trisoliv syrup in liver diseases might be due to the synergistic action of its ingredients, which had been well documented in various experimental and clinical studies by various researchers. The leaf extract of plant Andrographis paniculata i.e.andrographolide has shown hepatoprotective effect on various models of drug and ethanol induced liver damage. 7, 8, 9, 1, 11 Andrographolide aids in digestion by exerting its choleretic action i.e. activity to stimulate the bile production by Sorbitol acts as a syrup base and also as a osmotic laxative to relieve constipation. In this 8 week study Trisoliv Syrup significantly improved the LFT. Serum total bilirubin TB (used initially) gradually and significantly reduced from a baseline of 6.35 ± 2.24 to.72 ±.29 mg/dl (p<.1) over a period of 8 weeks. 86.95% patients achieved normal serum TB level at the end of study and 12.95% patients were required to continue Trisoliv Syrup till it comes within normal limits. Similarly SGOT reduced from a baseline of 122.5 ± 19.7 to 28.67 ± 8.4 IU/L (p<.1) gradually over a period of 8 weeks. liver 12. Andrographolide was found to be more SGPT also showed a statistically significant potent than silymarin; a standard reduction to 27.43 ± 8.65 from a baseline of 151.4 hepatoprotective agent in animal study to protect hepatocye against paracetamol induced damage. The antioxidant effect of andrographolide could be due to its ability to activate antioxidant enzymes that catalyze the reaction of oxidants and ± 37.13 IU/L (p<.1) at the end of trial. Similar finding was reported by Chaturvedi et al where andrographolide efficacy was evaluated in 2 patients suffering from infective hepatitis.8 % of patient reported to be cured and 2 % relieved are effective in severe liver damage 14. after treatment with andrographolides 18. Andrographolides are safe, non toxic and strong As subjective improvement of the clinical natural anti-oxidant in comparison with other symptoms is equally important, we evaluated the phyto-antioxidant 15.Tricholine citrate offers major clinical symptoms like loss of appetite, lipotropic action because of its activity to remove excess fat from the liver and prevents excessive fat deposition in the liver 16. The functions of choline fatigue, and jaundice symptoms on a predefined scale of to 3 score. At the end of 8 weeks study all the clinical symptoms score significantly which include methyl group metabolism, lipid reduced from baseline. 86.96% of patients transport, membrane phospholipids structure reported good to excellent efficacy and 82.61% of formation. Pathological consequence of choline deficiency includes fatty liver, liver cell death, liver cell proliferation, and liver cell cancer. Fatty liver due to choline deficiency appears to occur via patients reported good to excellent tolerability on global assessment scale.thus the study proves that Trisoliv Syrup is significantly efficacious and safe in patients suffering from various liver dysfunctions. ---------------------------------------------------------------------------------------------------------------------------------------------- Abbreviations Liver Function Test LFT SGOT Serum Glutamic Oxaloacetic Transaminase SGPT AST ALT SAP SD Serum Glutamic Pyruvic Transaminase Aspartate aminotransferase Alanine aminotransferase Serum Alkaline Phosphtase Standard Deviation
Page11 IJPBS Volume 2 Issue 1 JAN-MARCH 212 1-11 REFERENCES 1) Ekong, V.E., 2 Onibere, E.A., 3 Imianvan, A.A. Fuzzy Cluster Means System for the Diagnosis of Liver Diseases. IJCST 211, Vol. 2, Issue 3,25-9 2) S Ganesh,Pralhad S Patki, SK Mitra Clinical evaluation of a herbal formulation in liver disorders Australian Journal of Medical Herbalism 29 21(1),1-14. 3) Arankalle, V. A., M. S. Chadha, et al.. "Changing epidemiology of hepatitis A and hepatitis E in urban and rural India (1982-98)." J Viral Hepat 21, 8(4): 293-33. 4) Craig, A. S. and W. Schaffner (24). "Prevention of hepatitis A with the hepatitis A vaccine." N Engl J Med 35(5): 476-81. 5) Vitral, C. L., C. F. Yoshida, et al. (1998). "Age-specific prevalence of antibodies to hepatitis A in children and adolescents from Rio de Janeiro, Brazil, 1978 and 1995. 6) Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat. Mar 24; 11(2):97-17. 7) Girish C, Koner BC, Jayanthi S, Rao KR, Rajesh B, Pradhan SC - Hepatoprotective activity of six polyherbal formulations in paracetamol induced liver toxicity in mice. Indian J Med Res May 29; 129: 569-578. 8) Handa SS, Sharma A - Hepatoprotective activity of andrographolide from Andographis paniculta against carbontetrachloride. Indian J Med Res 199; 92: 276-83. 9) Koul IB, Kapil A - Effect of diterpenes from Andrographis paniculata on antioxidant defense system and lipid peroxidation. Indian J Pharmacol 1994; 26: 296-3. 1) Handa SS, Sharma A - Hepatoprotective activity of andrographolide against galactosamine & paracetamol intoxication in rats. Indian J Med Res 199; 92: 284-92. 11) Choudhury BR, Poddar MK - Andrographolide and Kalmegh (Andrographis paniculata) extract: in vivo and in vitro effect on hepatic lipid peroxidation. Methods Find Exp Clin Pharmacol 1984; 6: 481-5. 12) Shukla B, Visen PK, Patnaik GK, Dhawan BN. Choleretic effect of andrographolide in rats and guinea pigs. Planta Med. 1992 Apr; 58(2):146-9. 13) Visen PK, Shukla B, Patnaik GK, Dhawan BN. Andrographolide protects rat hepatocytes against paracetamol-induced damage. J Ethnopharmacol. 1993 Oct;4(2):131-6. 14) N.Trivedi, U.Rawal, B. Patel.Hepatoprotective effect of andrographolide against hexachlorocyclohexane-induced oxidative injury. Integr Cancer Ther. 27 Sep; 6(3):271-8. 15) Niranjan A, Tewari S.K., Lehri A, Biological activities of Kalmegh (Andrographis paniculata Nees) and its active principles A review, Indian J of Nat Prod and Res, 21; 1(2): 125-135. 16) Canty DJ, Zeisel SH. Lecithin and choline in human health and disease. Nutrition Reviews, 1994 52(1):327-39. 17) Ghoshal AK, Farber E. Choline deficiency lipotrope deficiency and the development of liver disease including liver cancer: a new perspective. Laboratory Investigation 1993, 68(3)255-6. 18) Chaturvedi et al - Effect of kalmegh in patients with Infective Hepatitis. J. Int. Inst. Ayurveda. 1983; 2: 28-215. * Corresponding Author Dr. Arif A.Faruqui General Manager-Medical Services, Medley Pharmaceuticals Ltd., D-2, MIDC, Andheri (E), Mumbai-93 Email- drfaruqui@medleylab.com